Alzheimer's disease (AD) is an irreversible, progressive brain disease characterized by the loss of cognitive functioning, e.g., memory and reasoning, and behavioral abilities. AD is estimated to affect more than 25 million people in the world and is reported in the 2010 World Alzheimer Report to have annual societal costs of US$604 billion, or 1% of the aggregated worldwide Gross Domestic Product (GDP). Existing AD medications aim to treat symptoms of AD only and do so rather poorly. Existing AD medications do not address the progression of the disease. New therapeutic agents that slow (or reverse) the disease and that target multiple aspects of the disorder are urgently needed.
Studies have shown that the etiology of AD includes a range of clear genetic predispositions involving amyloid precursor protein (APP), Tau phosphorylation, gamma-secretase (GS), apolipoprotein E (ApoE) and genes involved in circadian rhythms. There is strong evidence which indicates the importance of Tau hyper-phosphorylation, excessive amyloid beta (Aβ) formation and desynchrony of circadian rhythms in Alzheimer's disease. There is also clear evidence of a cell loss in the suprachiasmatic nucleus, the brain region involved in regulating circadian rhythms that coincides with development of the dementia stage of AD. AD patients suffer a plethora of symptoms including serious and progressive cognitive decline, sleep disturbances and agitation.
Casein Kinase 1 is a member of a unique class of protein serine/threonine kinases that are only distantly related to other kinase families. Comparing CK1 sequence identities to other kinase families, glycogen synthase kinase 3 (GSK3) is the closest related kinase outside the CK1 family and is only 20% identical in the catalytic domain. The CK1 family has seven isoforms with various splice variants. The role of CK1 in AD is substantially documented in recent reviews. See Buee et al., Brain Res. Rev. (2000) 33(1):95-130; See also Perez et al., Med. Res. Rev. (2010) 31(6):924-54. It has been observed that CK1 delta mRNA is elevated 30-fold in the hippocampus of AD patients' brains. Yasojima et al., Brain Res. (2000) 865(1):116-20. The beneficial effect of CK1 inhibitors to reverse Aβ formation has also been shown. Flajolet et al., Proc. Natl. Acad. Sci. U.S.A. (2007) 104(10):4159-64. With regard to the phosphorylation of various Tau forms, there are multiple sites of phosphorylation of Tau and a number of putative Tau kinases are involved. Although the role of various kinases in this process is complex, the importance of critical priming kinases is generally accepted as driving the hyper-phosphorylation co-incident with the formation of paired helical filaments (PHF) that are the universal pathology associated with AD. It is well documented that CK1 is a “major Tau kinase” with priming functions and is associated with paired helical filaments (PHF). Hanger et al., J. Biol. Chem. (2007) 282(32):23645-54. Most importantly, there is substantial evidence for a fundamental role of CK1 controlling circadian rhythm and metabolic state through phosphorylation and regulation of a series of transcription factors including CLOCK, BMAL-1, and Perl-3; with CK1 and CK2 collectively considered the “clock genes”. Ebisawa T., J. Pharmacol. Sci. (2007) 103(2):150-4. CK1 delta and epsilon gene variations are also associated with circadian rhythms changes.
Highly specific CK1 inhibitors have been developed and have served to further validate the role of CK1 in AD related pathologies. Several examples of potent and selective inhibitors are known. Using potent and selective CK1 inhibitors in rodent and monkey animal models, profound influences on phase shifts in circadian rhythms are discovered that substantially validate the hypothesis of CK1 involvement in the biological clock. Sprouse et al., Psychopharmacology (Berl) (2010) 210(4):569-76; Sprouse et al., Psychopharmacology (Berl) (2009) 204(4):735-42. All of these studies therefore support the critical role of CK1 as therapeutic target in AD.
In view of the important role of CK1, further potent and selective CK1 inhibitors are needed in the fight against AD and other CK1 related diseases.